Novel process

ABSTRACT

Compounds of structure (1) are obtained by reduction of compounds of the structures (2a), (2b), (4a), (4b).  
                 
 
     Compounds of structure (1), especially where Z is a hydrogen atom or a 3,4-methylenedioxyphenyl group, are important intermediates for inter alia paroxetine.

[0001] The present invention relates to a new process for preparingpharmaceutically active compounds and intermediates therefor.

[0002] Pharmaceutical products with antidepressant and anti-Parkinsonproperties are described in U.S. Pat. No. 3,912,743 and U.S. Pat. No.4,007,196. An especially important compound among those disclosed isparoxetine, the (−) trains isomer of4-(4′-fluorophenyl)-3-(3′,4′-methylenedioxy-phenoxymethyl)-piperidine.This compound is used in therapy as the hydrochloride salt to treatinter alia depression, obsessive compulsive disorder (OCD) and panic.

[0003] This invention aims to overcome disadvantages in the existingprocesses for preparation of such compounds and so to providealternative processes for their manufacture.

[0004] This invention has been developed on the basis that compounds ofstructure (1) below are either valuable chemical intermediates usefulfor the manufacture of important medicinal products, for exampleparoxetine hydrochloride, or are themselves active compounds, such asdisclosed in U.S. Pat. No. 3,912,743 and U.S. Pat. No. 4,007,196.

[0005] By reference to Example 4 of U.S. Pat. No. 4,007,196, paroxetinemay be prepared from a compound of structure (1) below in which R ismethyl, and Z is hydrogen, that is4-(4′-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine, by reaction with3,4-methylenedioxyphenol followed by demethylation. In the same Example,4-(4′-fluorophenyl)-3-hydroxymethyl-1-methyl piperidine is prepared byreduction of4-(4′-fluorophenyl)-3-hydroxymethyl-methyl-1,2,3,6-tetra-hydropyridine(II), which is in turn prepared from4-(4′-fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (III), byreaction with formaldehyde.

[0006] Alternative processes for the preparation of4-(4′-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine are given inEP-A-0223334, by reduction of compounds of structure (A)

[0007] in which Z is alkyl and R is H. alkyl or aralkyl.

[0008] The above described processes produce compounds of structure (1)as a mixture of enantiomers. Therefore conversion of compounds ofstructure (1) to useful pharmaceuticals, such as paroxetine i.e. the (−)trans isomer of4-(4′-fluorophenyl)-3-(3′,4′-methylenedioxy-phenoxymethyl)-piperidine,will normally require a resolution stage, as described in EP-A-0223334.

[0009] This invention provides a process for the preparation of4-aryl-piperidines of structure (1)

[0010] in which R is hydrogen or an alkyl, aralkyl, aryl, acyl,alkoxycarbonyl, arylalkoxycarbonyl aryloxycarbonyl group, and Z′ is a3,4-methylenedioxyphenyl group,

[0011] which comprises reduction of a compound of structure (2a) or (2b)

[0012]  in which

[0013] Y is oxygen or sulphur, and

[0014] R and X are as defined above and Z is hydrogen or an alkyl.aralkyl or aryl group, and where Z is other than a3,4-methylenedioxyphenyl group thereafter converting Z to3,4-methylenedioxyphenyl.

[0015] This invention also provides a process for the preparation of4-aryl-piperidines of structure (1)

[0016] in which R is hydrogen or an alkyl, aralkyl, aryl, acyl,alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl group, and Z ishydrogen or an alkyl. aralkyl or aryl group, most suitably where Z is ahydrogen atom or a 3,4-methylenedioxyphenyl group,

[0017] which comprises reduction of a compound of structure (2a) or (2b)

[0018]  in which

[0019] Y is oxygen or sulphur, and

[0020] R, X, and Z are as defined above.

[0021] When Z incorporates an aryl group, the aryl group, for examplephenyl, may be optionally substituted by one or more groups such ashalogen or alkyl or alkoxy, or by two substituents linked to form afused ring. For example, an especially suitable substituent Z is3,4-methylenedioxyphenyl, as found in paroxetine. Alkyl groups,including alkyl groups that are part of other moieties such as alkoxy oracyl, are typically C₁₋₆, especially C₁₋₄ groups.

[0022] Compounds of structure (2a) and (2b) are believed to be novel andform part of this invention, especially compounds in which X is H, Z isH or 3,4-methylenedioxyphenyl and R is H or C₁₋₄alkyl, especiallymethyl.

[0023] In a first aspect of the process of this invention compounds ofstructure (2a) or (2b) are reduced to give compounds of structure (1) inwhich Z is H, that is 3-hydroxymethyl-4-aryl piperidines. Reduction maybe accomplished by hydrogenation at atmospheric or above atmosphericpressure using a variety of known catalysts, or using hydride reagentssuch as lithium aluminium hydride and sodium borohydride, or by acombination of known methods. A particularly useful aspect of thisinvention is the transformation of 4-aryl-3-carboxyalkyl-1-(optionallysubstituted)-piperidines to 4-aryl-3-hydroxymethyl-1-(optionallysubstituted)-piperidines.

[0024] It will be appreciated that reduction of esters or carboxylicacids of structure (2) may be carried out stepwise and an intermediatemay be isolated, for example a carboxaldehyde, and the reduction ofthese intermediate compounds to a compound of structure (1) is alsoincluded in the scope of this invention.

[0025] Intermediate carboxaldehydes are believed to be novel and formpart of this invention. A particularly valuable intermediate is4-(4-fluorophenyl)-5-oxopiperidine-3-carboxaldehyde.

[0026] In a second aspect of the process of this invention compounds ofstructure (2a) and (2b), where Z is not H. are reduced to ethers ofstructure (1). This may be accomplished by the use of known selectivereagents such as diborane and DIBAL, or by Raney nickel desulphurizationof a thionoester intermediate. A particularly advantageous ether for themanufacture of paroxetine is the 3,4-methylenedioxyphenyl ether.

[0027] Following the reduction to give an ether of structure (1), eitheror both the groups Z and R may be subsequently converted to a differentgroup Z or R by conventional means, in order to produce the, desiredpharmaceutical agent. For example, in the preparation of paroxetine, itmay be appropriate to convert Z=H to Z=3,4-methylenedioxyphenyl and/orR=C₁₋₄alkyl to R=H. This aspect is also included in the scope of thisinvention.

[0028] One advantageous aspect of this process is that a singleenantiomer of the intermediate (2) may be prepared either byenantioselective synthesis or from a chiral precursor, in which case theresolution noted above may be avoided entirely or transferred to anearly stage in the overall process.

[0029] Starting materials of structure (2a), where Y is oxygen, may beprepared conveniently by carboxyalkylation of a 4-aryl-piperidine-2-oneprecursor, which may in turn be obtained from the reaction of anactivated alkyl 3-aryl-5-hydroxyvalerate with an amine. In aparticularly advantageous embodiment of this invention the alkyl3-aryl-5-hydroxyvalerate is prepared as a single enantiomer by selectivereduction of a 3-arylglutarate mono-ester obtained by enzymatichydrolysis of the pro-chiral dialkyl 3-arylglutarate, for example usingpig liver esterase to obtain S-enantiomers and -chymotripsin to obtainR-enantiomers. Suitable dialkyl 3-arylglutarates may be obtained by, forexample, reaction of 4-fluorobenzaldehyde with methyl acetoacetate.

[0030] The ester group at the 3-position or a group convertible to anester group may already be present in the starting material or may beintroduced for example by reaction of a 2-piperidone of structure (3)firstly with a strong base, such as sodium hydride or lithiumhexamethyldisilazide followed by a carboxylating agent, such as achloroformic ester or thiono chloroformic ester.

[0031] Compounds with structure (2b) where Y is oxygen may be preparedby, for example, reductive cyclisation of2-cyano-3-(4′-fluorophenyl)-glutarate esters. A similar preparation hasbeen described for the preparation of3-ethoxycarbonyl-4-(3′-methoxyphenyl)-2-piperidone (Journal of OrganicChemistry (1977) volume 42, pages 1485-1495), but this procedure hadbeen found to be unsuitable for the preparation of compounds withstructure (2b) and results in a complex mixture of products. A new andefficient process has now been discovered in which2-cyano-3-(4′-fluorophenyl)glutarate esters, especially diethyl2-cyano-3-(4′-fluorophenyl)glutarate, are hydrogenated in 1,4-dioxane.Such compounds may be prepared by reaction of, for example, ethylcyanoacetate and ethyl 4-fluorocinnamate in sodium ethoxide.

[0032] Compounds of structure (2a) and (2b) where Y is sulphur can beprepared from the cyclization of analogous thionoesters or by thereaction of piperidones with sulphurizing reagents such as Lawesson'sreagent or phosphorus pentasulphide, as described in Organic Syntheses(1984), volume 62, page 158 and the Journal of Organic Chemistry (1981)volume 46, page 3558. Reduction of the thio-piperidones may beaccomplished stepwise, particularly if a reagent such as Raney nickel isused for the first stage. The resulting 4-aryl-3-carboxyalkylpiperidinesmay then be separately reduced to compounds of structure (1) byconventional reduction, most suitably with hydride reagents such aslithium aluminium hydride.

[0033] Suitable starting materials of structure (2) can be prepared bythe manner described above or by transesterification of intermediateesters.

[0034] It will be appreciated that the reduction of compounds ofstructure (2) to give compounds of structure (1) may take place stepwisevia, inter alia, compounds of structure (2c) and (2d)

[0035] and the reduction of these intermediate compounds, when producedby this process is also included in the scope of this invention.

[0036] Compounds of structure (2c) where X is hydrogen, Z is methyl, andR is hydrogen or C₁₋₄alkyl, were described in U.S. Pat. No. 4,007,196,though no procedure was described which is satisfactory for large scalemanufacture. These problems have been overcome in the pendingapplication GB9700690.2. The preparation of compounds of structure (2c),where R and Z are alkyl, by reduction of quaternary pyridinium saltshave also been described in EP 0219934.

[0037] Compounds of structure (2c) other than those described in theabove mentioned patent applications and compounds of structure (2d) arenovel and form part of this invention. Particularly important compoundsof structure (2c) are those where Z is aryl, especially3,4-methylenedioxyphenyl, which may inter alia be prepared by selectivereduction of compounds (2a) or (2b) or by transesterification of othercompounds (2c). Compounds of Structure (2c) and (2d) may be reducedfurther to compounds of structure (1).

[0038] Alternatively, interrupted or selective reduction of compounds(2a) and (2b) may give rise to novel intermediate alcohols or ethers ofstructure (4a) or (4b) which may be isolated, and which also form partof this invention.

[0039] In a preferred method for the preparation of compounds ofstructure (4a) and (4b), compounds of structure (2a) and (2b) are firstconverted into thioesters which are desulphurised with, for example,Raney nickel. The intermediate thiono esters are also novel and formpart of this invention.

[0040] Compounds of structure (4a) and (4b) may also be separatelyprepared by reactions analogous to those described above for thepreparation of compounds of structure (2a) and (2b) and employed in theprocesses of this invention. For example a carbinol of structure (4a)may be prepared by hydroxymethylation of compound (3), and an ethergroup may be introduced by reaction of (3) with a chloromethyl ether.

[0041] Particularly important compounds of structure (4a) and (4b) arethose where Z is 3,4-methylenedioxyphenyl, and especially where X and Rare both hydrogen. Compounds of structure (4) may be reduced further tocompounds of structure (1).

[0042] The novel compounds of structure (4) may also be prepared byother methods such as etherification of (4) where Z is hydrogen, orreductive alkylation of aldehydes.

[0043] Many of the intermediate compounds in the processes of thisinvention are novel, and such intermediates form another aspect of thisinvention.

[0044] In a further aspect of the invention, a compound of structure (1)in which Z is a hydrogen atom obtained by processes of this inventionmay be converted to an active compound disclosed in U.S. Pat. No.3,912,743 and U.S. Pat. No. 4,007,196 using conventional proceduresdisclosed therein.

[0045] In particular the compound of structure (1) in which in which Zis a hydrogen atom may be used to prepare paroxetine. The paroxetine ispreferably obtained as the hydrochloride salt and most preferably as thehemihydrate of that salt, as described in EP-A-0223403. The presentinvention includes within its scope the compound paroxetine,particularly paroxetine hydrochloride, especially as the hemihydrate,when obtained via any aspect of this invention, and any novelintermediates resulting from the described procedures.

[0046] Paroxetine obtained using this invention may be formulated fortherapy in the dosage forms described in EP-A-0223403 or WO96/24595,either as solid formulations or as solutions for oral or parenteral use.

[0047] Therapeutic uses of paroxetine, especially paroxetinehydrochloride, obtained using this invention include treatment of:alcoholism, anxiety, depression, obsessive compulsive disorder, panicdisorder, chronic pain, obesity, senile dementia, migraine, bulimia,anorexia, social phobia, pre-menstrual syndrome (PMS), adolescentdepression, trichotillomania, dysthymia, and substance abuse, referredto below as “the Disorders”.

[0048] Accordingly, the present invention also provides:

[0049] a pharmaceutical composition for treatment or prophylaxis of theDisorders comprising paroxetine or paroxetine hydrochloride obtainedusing the process of this invention and a pharmaceutically acceptablecarrier.

[0050] the use of paroxetine or paroxetine hydrochloride obtained usingthe process of this invention to manufacture a medicament in solid orliquid form for the treatment or prophylaxis of the Disorders; and

[0051] a method of treating the disorders which comprises administeringan effective or prophylactic amount of paroxetine or paroxetinehydrochloride obtained using the process of this invention to a personsuffering from one or more of the Disorders.

[0052] This invention is illustrated by the following Examples.

EXAMPLE 1

[0053] Dimethyl 3-(4′-fluorophenyl)glutarate

[0054] 4-Fluorobenzaldehyde (75 ml), methyl acetoacetate (150 ml),piperidine (10 ml). and methanol (235 ml), were stirred for 8 hours atambient temperature. The precipitate was filtered, washed twice withcold methanol (2×75 ml), resuspended in methanol (150 ml), treated witha mixture of a 25% solution of sodium methoxide in methanol (650 ml) andwater (54 ml), and heated at reflux for 7 hours. After cooling, solvent(500 ml) was removed by vacuum distillation, water (1 litre) was added,and a further quantity of solvent removed by distillation (100 ml). Themixture was extracted with tert-butyl methyl ether (400 ml), acidifiedto pH less than 3 with concentrated hydrochloric acid, and extractedwith tert-butyl methyl ether (3×300 ml). The extracts were evaporatedand the tert-butyl methyl ether replaced by methanol (800 ml).Concentrated hydrochloric acid (10 ml) was added, the mixture heated atreflux for 12 hours. and the solvent partially removed by evaporation.Dilution with water (75 ml) gave crystals of dimethyl3-(4′-fluorophenyl)glutarate. Yield after drying 124.1 g (71%).

EXAMPLE 2

[0055] S-3-(4′-fluorophenyl)glutaric acid monomethyl ester

[0056] A solution of dimethylformamide in water (20%. 7 litres) wasadjusted to pH 7.0 with 1.0 M phosphate buffer, and dimethyl3-(4′-fluorophenyl)glutarate (160 g) added. The mixture was held at 37°C. pig liver esterase (46 ml, 96,000 U) added, and the reactioncontinued for 24 hours at constant temperature and pH. The mixture wascooled, acidified to below pH 3 with hydrochloric acid, and extractedwith tert-butyl methyl ether (3×1500 ml). The extracts were washed withdilute hydrochloric acid (2×1 litre), reduced to about 1 litre byevaporation. treated with hexane (100 ml), and cooled to 0° C. tocrystallize the product. The supernatant liquors were decanted,evaporated to 200 ml. and treated with hexane (50 ml) to give furthercrystals. The yield of crystalline (S-enantiomer) mono-ester afterdrying was 118.8 g (78%).

[0057] The R-enantiomer is obtained by an analogous procedure using-chymotrypsin (Can. J. Chem., 1994. 72(11), 2312).

EXAMPLE 3

[0058] R-1-benzyl-3-(4′-fluorophenyl)-piperidine-2-one

[0059] A solution of S-3-(4′-fluorophenyl)glutaric acid monomethyl esterin tetrahydrofuran (800 ml) was treated with lithium hydride (2.65 g)and heated at reflux for 1 hour. After cooling, a lithium borohydridesolution (108 ml, 2 molar) was added slowly and the mixture heated atreflux for 12 hours, then cooled to ambient temperature.Dimethylformamide (400 ml) and methyl sulphate (56.6 ml) were added andthe mixture heated at reflux for 5 hours, cooled, quenched with methanol(80 ml), and after 30 minutes diluted with toluene (1500 ml) and washedwith 10% ammonium chloride solution (3×800 ml). The toluene phase wasevaporated to about 400 ml, diluted with toluene (1 litre) andevaporated again to 400 ml; this was repeated twice more.

[0060] Toluene (600 ml) and triethylamine (96 ml) were added to thecrude methyl 3-(4′-fluorophenyl)-5-hydroxyvalerate, the mixture cooledto 0° C. then slowly treated with methanesulphonyl chloride (32 ml). Themixture was stirred for 45 minutes at 0° C., filtered through silica,and the cake washed with toluene (100 ml). Triethytamine (100 ml),benzylamine (40 ml), and sodium iodide (2 g) were added to the filtrateand the mixture heated at reflux for 20 hours, then cooled and washedwith 2 molar hydrochloric acid (3×600 ml) and saturated sodium hydrogencarbonate (2×500 ml). The resulting solution of crudeR-1-benzyl-3-(4′-fluorophenyl)-piperid-2-one was evaporated to about 300ml and diluted with heptane (50 ml) to induce crystallization.

[0061] Yield of dried product 52.6 g (56%,>99%).

EXAMPLE 4

[0062] S-1-benzyl-3-(4′-fluorophenyl)-piperidine-2-one

[0063] S-1-benzyl-3-(4′-fluorophenyl)-piperidine-2-one is prepared fromS-3-(4′-fluorophenyl)glutaric acid monomethyl ester by an analogousprocedure in which the initial reduction is carried out with borane.Similarly R-1-benzyl-3-(4′-fluorophenyl)-piperidine-2-one may beprepared from R-3-(4′-fluorophenyl)glutaric acid monomethyl ester.

EXAMPLE 5

[0064]trans-(4R)-1-benzyl-3-carboxymethyl-4-(4′-fluorophenyl)-piperidine-2-one

[0065] A solution of R-1-benzyl-4-(4′-fluorophenyl)-piperidine-2-one(2.0 g) in toluene (40 ml) was treated with sodium hydride (0.704 g, 60%dispersion in oil) and dimethyl carbonate (3.0 ml), and heated at refluxfor 14 hours. After cooling the reaction mixture was quenched with ice,treated with methanol (15 ml), and potassium carbonate (0.5 g) andstirred for 1 hour. Toluene (100 ml) was added and the phases wereseparated. The organic phase was washed with 1 molar hydrochloric acid(2×50 ml), saturated sodium hydrogen carbonate solution (2×50 ml), andwater (50 ml). The organic phase was evaporated and the crudetrans-(4R)-1-benzyl-3-carboxymethyl4-(4′-fluorophenyl)-piperidine-2-onecrystallised from tert-butyl methyl ether and hexane. Yield 1.56 g(65%).

EXAMPLE 6

[0066] Preparation oftrans-(4R)-1-benzyl-4-(4′-fluorophenyl)-3-hydroxymethyl piperidine

[0067] A solution of trans(4R)-1-benzyl-3-carboxymethyl-4-(4′-fluorophenyl)-piperidine-2-one (1.97g) in tetrahydrofuran (20 ml) was treated with borane-tetrahydrofurancomplex (19.6 ml. 1 molar) and heated at reflux for 6 hours. Aftercooling, the reaction was quenched with 1 molar hydrochloric acid, thenstirred and heated at reflux for a further 1 hour. The mixture wascooled to ambient temperature, the pH adjusted to 9 with 1 molar sodiumhydroxide, and extracted with ethyl acetate (3×20 ml). The combinedorganic extracts were washed with saturated sodium chloride andevaporated to givetrans-(4R)-1-benzyl-4-(4′-fluorophenyl)-3-hydroxymethylpiperidine (1.59g, 92%).

EXAMPLE 7

[0068] Preparation of Paroxetine Hydrochloride

[0069] a)trans-(4R)-1-benzyl-4-(4′-fluorophenyl)-3-hydroxymethylpiperidine (9.65g), p-toluenesulphonyl chloride (6.18 g), dimethylaminopyridine (0.1 g),and triethylamine (5.0 ml) in toluene (150 ml) were stirred for 42 hoursat ambient temperature. The mixture was diluted with toluene (100 ml),washed with saturated sodium hydrogen carbonate (3×150 ml) and water(100 ml). The organic layer was evaporated to minimum volume, anddiluted with toluene (100 ml). A solution of sesamol (4.28 g) indimethyl formamide (150 ml) was reacted with sodium hydride (1.26 g),added to the activated carbinol solution, and the mixture heated at 60°C. for 16 hours. The mixture was cooled, diluted with toluene (200 ml),washed with 1 molar sodium hydroxide (2×100 ml) and water (2×100 ml),and evaporated to an oil. Yield 9.83 g (79%).

[0070] b) The oil from Example 7 (a) (4.0 g) was dissolved inisopropanol (40 ml) and acetic acid (4 ml) and hydrogenated with 5%palladium on charcoal catalyst (2.0 g) at 70 psi and 50° C. for 2 hours.The cooled mixture was filtered through celite, the celite washed withisopropanol (40 ml) and the filtrate diluted with toluene (100 ml). Thesolution was washed with saturated sodium hydrogen carbonate (2×100 ml).1 molar sodium hydroxide (100 ml), then water (100 ml). and finally withsaturated sodium chloride (100 ml). The organic phase was evaporated tolow volume (15 ml), treated with concentrated hydrochloric acid (2 ml)and isopropanol (15 ml). The crystalline paroxetine hydrochloride wasisolated, washed and dried. Yield 2.1 g.

EXAMPLE 8

[0071] Diethyl 2-cyano-3-(4-fluorophenyl)-glutarate

[0072] A mixture of ethyl cyanoacetate (13.56 g) and ethyl4-fluorocinnamate (19.4 g) was added to a solution of sodium ethoxide(2.3 g sodium in 50 ml ethanol) at 60° C. over 2-3 minutes and themixture heated under reflux for 1 hour then cooled to 5° C. Glacialacetic acid (6 ml) was added slowly to the reaction mixture at below 5°C. The bulk of the ethanol was removed by distillation at reducedpressure the residue diluted with water (40 ml), extracted with toluene(3×30 ml), and the combined organic phases dried over anhydrousmagnesium sulphate. The solution was filtered, evaporated to an oil(28.6 g), and distilled at 166-180° C. at 3.5 mbar to produce diethyl2-cyano-3-(4-fluorophenyl)-glutarate (23 g, 74% yield. 98% purity).

EXAMPLE 9

[0073] 3-Carboxyethyl-4-(4′-fluorophenyl)-piperidine-6-one.

[0074] Diethyl 2-cyano-3-(4-fluorophenyl)-glutarate (15.3 g), platinumoxide (0.57 g), and hydrogen chloride gas in dioxane (0.1 mole in 50 ml)were hydrogenated at 185 psi and 60° C. for 6.5 hours. The product wascooled, filtered, and evaporated, and the residue was dissolved inchloroform (130 ml) and washed with saturated sodium bicarbonate (200ml). The solution was dried and passed through activated carbon (DarcoG-40) to remove colloidal platinum and evaporated to give crude3-carboxyethyl-4-(4′-fluorophenyl)-piperidine-6-one. This product wasrepeatedly treated in ethyl acetate solution with activated carbon togive a purified product as a mixture of isomers (9.3 g, 70%, 95.6%purity).

EXAMPLE 10

[0075] 3-Carboxyethyl-4-(4′-fluorophenyl)-piperidine-6-one.

[0076] Diethyl 2-cyano-3-(4-fluorophenyl)-glutarate (85.0 g, 0.22 mol),platinum oxide (2.1 g), and 4 molar hydrogen chloride gas in dioxane(112 ml, 0.45 mol) were stirred in a Parr apparatus under hydrogen(90-195 psi) at 60° C. for 18 hours. The residue was filtered andevaporated and then dissolved in chloroform (300 ml). washed withsaturated sodium bicarbonate solution (250 ml), dried, filtered throughactivated carbon (Darco G-40) to remove colloidal platinum, andevaporated to give the title compound (72.1 g, 84%) as an oil whichcrystallised on standing. Recrystallisation from hexane-dichloromethanegave a product with a cis/trans ratio 88:12, m.p. 139-141° C.

EXAMPLE 11

[0077] 4-(4-Fluorophenyl)-3-hydroxymethylpiperidine

[0078] Borane-tetrahydrofuran complex (1.0 molar solution intetrahydrofuran (10.8 ml, 10.8 mmol) was added over 20 hours in 3 stages(in 3.6 mmol portions) at a rate of 7 ml/hour by means of a syringe pumpto a solution of 4-(4-fluorophenyl)-3-carboxyethylpiperidin-6-one (0.53g, 2 mmol, trans/cis˜1:1) in tetrahydrofuran (3 ml) at 26° C. Thereaction mixture was stirred for 1 hour after addition of the lastportion of the borane solution, then quenched with 3.5 ml 30% aqueouspotassium carbonate solution. The phases were separated and the aqueousphase extracted with diethyl ether (25 ml). The organic phases werecombined and evaporated to yield 0.43 g of the title compound. Yield80%.

EXAMPLE 12

[0079] 4-(4-Fluorophenyl)-3-hydroxymethylpiperidine

[0080] Lithium aluminum hydride (1.0 molar solution in tetrahydrofuran,0.75 ml, 0.75 mmol) was added gradually to a solution oftrans-4-(4-fluorophenyl)-3-carboxyethylpiperidin-6-one (0.25 g, 0.836mmol) in tetrahydrofuran (3 ml) keeping the temperature below 25° C. Thereaction mixture was stirred for 1 hour at 25° C., then quenched with 1drop of water, followed by 2 drops 15% sodium hydroxide solution, andfinally with 5 drops of water. Extraction with dichloromethane (35 ml)followed by exaporation of the dichloromethane phase gave 0.21 g of thetitle compound. Yield 76%.

EXAMPLE 13

[0081] 4-(4-Fluorophenyl)-3-carboxyethylpiperidine

[0082] 4-(4-fluorophenyl)-3-carboxyethylpiperidin-6-one (12.0 g 0.045mol. trans/cis-ratio˜1:1) was added in one portion to a solution oftrimethyloxonium fluoroborate (12.0 g, 0.081 mol) in dichloromethane (80ml) and the resulting solution stirred, at 14-18° C., for 60 hours underan argon atmosphere. The solvent was removed in vacuo, and then theresidue was dissolved in absolute ethanol (100 ml), heated to 45° C. andtreated with sodium borohydride (10.0 g, 0.26 mol) in 1.0 g portions,allowing the mixture to boil under reflux. Most of the solvent wasevaporated and the residue quenched with water (60 ml) followed byconcentrated hydrochloric acid. After neutralization with 10% sodiumbicarbonate solution the products were extracted with dichloromethane(150 and 50 ml). The extracts were dried with anhydrous sodium sulphate,filtered, and evaporated to afford the title compound as a cis/transmixture (1:1). Yield 75%. A portion of the product was purified bycolumn chromatography (silica gel, eluted with ethylacetate-triethylamine, 98:2).

[0083] Under the same conditions,trans-4-(4-fluorophenyl)-3-carboxyethylpiperidine was prepared fromtrans-enriched 4-(4-fluorophenyl)-3-carboxyethylpiperidin-6-one.

EXAMPLE 14

[0084] 3-Carboxy-4-(4-fluorophenyl)piperidine-6-one.

[0085] A solution of 4-(4-fluorophenyl)-3-carboxyethylpiperidin-6-one(2.0 g, 0.0075 mol) in ethanol (10 ml) was added to a solution of sodiumhydroxide (0.4 g, 0.01 mol) in 95% ethanol and the mixture brought toreflux and stirred for 2.5 hours. The solvent was then removed byevaporation at reduced pressure, and the residue neutralized with 10%aqueous hydrochloric acid (25 ml) and extracted with ethyl acetate (3×20ml). After separation, the combined organic phases were dried withanhydrous sodium sulphate, filtered, and evaporated to give only 0.1 gof a white solid. The aqueous phase was therefore lyophilized and theresidue extracted with hot methanol. The residue, consisting ofinorganic salts. was discarded while the methanol extracts were combinedand evaporated at reduced pressure to give the title compound (1.34 g,75%).

EXAMPLE 15

[0086]4-(4-Fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxycarbonyl]-piperidine-6-one.

[0087] A solution of 4-(4-fluorophenyl)-3-carboxyethylpiperidin-6-one(0.5 g, 1.88 mmol. trans/cis ratio 56:44) in ethanol (10 ml) was addedto a solution of sodium hydroxide (0.08 g, 2 mmol) in 95% ethanol (5 ml)and the mixture heated for 4 hours at 60° C. The solvent was removed atreduced pressure and the residue of water removed by distillation withtoluene. The residue was suspended in dichloromethane (5 ml), treatedwith a solution of thionyl chloride (0.24 g, 2 mmol), and the mixturewas brought to reflux. After 1 hour evolution of sulphur dioxide ceased,so the mixture was cooled to room temperature and treated with pyridine(0.16 g, 2 mmol) followed by a solution of sesamol (0.24 g, 1.75 mmol)in chloroform (2.5 ml). The resulting mixture was brought to reflux,heated for 4 hours, and stirred at ambient temperature for 2 days. Thesolvent was then removed at reduced pressure and the residue treatedwith water (5 ml), then extracted with ethyl acetate (20 and 10 ml). Theorganic extracts were combined, washed with brine (20 ml), dried overanhydrous sodium sulphate, filtered and evaporated to give the titlecompound (0.32 g).

EXAMPLE 16

[0088] 4-(4-Fluorophenyl)-3-formylpiperidine-6-one.

[0089] DIBAL-H (4.03 ml, 6 mmol) was added gradually at a race of 5.6ml/hour, by means of a syringe pump, to a solution of3-carboxyethyl-4-(4-fluorophenyl)-piperidine-6-one (0.53 g, 2 mmol) in 4ml tetrahydrofuran at −70° C. under an argon atmosphere. The reactionmixture was stirred for 1 hour at −70° C. then quenched with a solutionof methanol (0.24 ml) in toluene (2 ml) at −70° C., followed by 0.12 mlwater at 0° C. After 30 minutes stirring at ambient temperature, the gelwhich formed was destroyed by the addition of 1.5 ml brine and thereaction mixture was extracted with diethyl ether (50 ml). The organicphase was separated, dried with anhydrous sodium sulphate, filtered andevaporated to yield the title compound (0.2 g) as a yellow oil. Theaqueous layer was basified with 10% aqueous sodium hydroxide andextracted with dichloromethane (20 ml). A further 0.08 g product wasisolated from the dichloromethane extract.

EXAMPLE 17

[0090] 4-(4-Fluorophenyl)-3-hydroxymethylpiperidine-6-one.

[0091] DIBAL-H (15.1 ml, 0.0225 mol) was added at a rate of 50 ml/hour,by means of a syringe pump, to a solution of3-carboxyethyl-4-(4-fluorophenyl)-piperidine-6-one (1.99 g, 0.0075 mol)in tetrahydrofuran (15 ml) at −70° C. under an argon atmosphere keepingthe temperature below 0° C. The mixture was allowed to warm to 23° C.and stirred for 45 minutes, then a solution of methanol (0.9 ml) intoluene (7.5 ml) was added to destroy the excess DIBAL-H. followed by30% potassium carbonate solution (8.5 ml), all below 30° C. The organicphase was separated, dried with anhydrous sodium sulphate, filtered, andevaporated to afford the title compound (1.54 g) as a slightly coloredoil, which was crystallized by trituration with ether. Yield 67%.

[0092] Recrystallization from ether-ethyl acetate gave a productwith >96% purity, m.p. 188.8-191.6° C.

EXAMPLE 18

[0093]4-(4-Fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine-6-one.

[0094] To a solution of4-(4-fluorophenyl)-3-hydroxymethylpiperidine-6-one (0.36 g, trans/cisratio >95:5) and dimethylethylamine (0.25 g) in dichloromethane (6 ml)was added a solution of benzenesulphonyl chloride (0.34 g, 0.25 ml. 1.94mmol) in dichloromethane (4 ml). The mixture was homogenized withN,N-dimethylformamide (1 ml) and stirred at ambient temperature for 5hours during which time more dimethylethylamine was added in aliquots(2.5 ml over 2.5 hours making a total of 0.5 ml). The mixture was thenquenched with water (15 ml), the phases separated, and the aqueous phaseextracted with dichloromethane (20 ml). The combined organic phases werewashed with brine (10 ml) and evaporated to give 0.56 g of theO-benzenesulphonate intermediate. This product was dissolved inN,N-dimethylformamide (6 ml), mixed with a solution of sesamol (0.25 g,1.81 mmol) in N,N-dimethylformamide (4 ml), and treated with 1 drop ofwater. Sodium methoxide (0.28 g, 5.14 mmol) was added slowly to thesolution, keeping the temperature at approximately 20° C., then thetemperature was raised to 50° C. and maintained for 6.5 hours. Themixture was then quenched with water (30 ml), the phases separated, andthe aqueous phase extracted with diethylether (3×50 ml). The combinedorganic extracts were washed with a 15% sodium hydroxide solution (2×35ml) and brine (50 ml), dried with anhydrous sodium sulphate, filtered,and evaporated to give crude4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine-6-one(0.24 g). This product was purified by column chromatography (silica geleluted with ethyl acetate/methanol gradient with 2% triethylamine).

EXAMPLE 19

[0095]4-(4-Fluorophenyl)-3-[(3,4methylenedioxyphenyl)oxymethyl]piperidine.

[0096] A solution of lithium aluminium hydride in tetrahydrofuran (1.0Msolution, 2 ml. 2.0 mmol) was added over ten minutes to a well stirredsolution of4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine-6-one(0.4 g, 0.96 mmol) in tetrahydrofuran (7 ml), maintaining thetemperature below 25° C. The reaction solution was stirred for 2 hoursand then quenched first of all with water (0.16 ml), then with 15%aqueous sodium hydroxide solution (0.1 ml), and finally with water again(0.4 ml). The reaction mixture was stirred for 0.5 hours to complete theprecipitation, diluted with dichloromethane (30 ml) and filtered. Thefiltrate was evaporated in vacuo to give the title product with atrans/cis ratio=72:28. Yield 90%.

[0097] Column chromatography on silica gel 60 (elution with a mixture ofethyl acetate:methanol:triethylamine=80:20:5) yielded a pure product asthe transisomer.

What is claimed is:
 1. A process for the preparation of4-aryl-piperidines of structure (1)

in which R is hydrogen or an alkyl, aralkyl, aryl, acyl, alkoxycarbonyl,arylalkoxycarbonyl, aryloxycarbonyl group, and Z′ is a3,4-methylenedioxyphenyl group, which comprises reduction of a compoundof structure (2a) or (2b)

in which Y is oxygen or sulphur, and R and X are as defined above and Zis hydrogen or an alkyl, aralkyl or aryl group, and where Z is ocherthan a 3,4-methylenedioxyphenyl group thereafter converting Z to3,4-methylenedioxyphenyl.
 2. A process for the preparation of4-aryl-piperidines of structure (1)

in which R is hydrogen or an alkyl, aralkyl, aryl, acyl, alkoxycarbonyl,arylalkoxycarbonyl, aryloxycarbonyl group, and Z is hydrogen or analkyl, aralkyl or aryl group, most suitably where Z is a hydrogen atomor a 3,4-methylenedioxyphenyl group, which comprises reduction of acompound of structure (2a) or (2b)

in which Y is oxygen or sulphur, and R, X, and Z are as defined above.3. A process according to claim 1, in which the reduction is carried outby catalytic hydrogenation at atmospheric or above atmospheric pressureor using hydride reagents.
 4. A process according to claim 1, in which acompound of structure (1) in which Z is alkyl, aralkyl or aryl isprepared by selective reduction of the ester group in a compound ofstructure (2a) or (2b) in which Z is alkyl, aralkyl or aryl.
 5. Aprocess for the preparation of 4-aryl-piperidines of structure (1)

in which R is hydrogen or an alkyl, aralkyl, aryl, acyl, alkoxycarbonyl,arylalkoxycarbonyl, aryloxycarbonyl group, and Z is hydrogen or analkyl, aralkyl or aryl group, especially a hydrogen atom or a3,4-methylenedioxyphenyl group, which comprises reduction of a compoundof structure (4a) or (4b)

where X is one or more of hydrogen or a readily reducible group such aschlorine, bromine or iodine, and R and Z are as defined above.
 6. Aprocess according to claim 1, in which the reduction is accomplished bycatalytic hydrogenation at atmospheric or above atmospheric pressure orusing hydride reagents.
 7. A compound of structure (2a) or (2b)

in which Y is oxygen or sulphur, and R, X, and Z are as defined inclaim
 1. 8. A compound of structure (4a) or (4b)

in which R, X, and Z are as defined in claim 1
 9. A compound ofstructure (4c) or (4d)

in which R and X are as defined in claim 1
 10. A compound of structure(1)

in which R is hydrogen and Z is 3,4-methylenedioxyphenyl, wheneverobtained by (a) a process according to claim 1, or (b) condensing acompound in which Z is hydrogen obtained by a process according to claim1 with 3,4-methylenedioxyphenol, and where necessary removing a group Rthat is other than hydrogen.
 11. A compound according to claim 9, in theform of a hydrochloride salt.
 12. A method of treating the Disorderswhich comprises administering an effective or prophylactic amount of acompound as claimed in claim 9 to a person suffering from one or more ofthe Disorders.